While many factors are involved in precipitating relapse in recovering drug addicts, life stressors are often reported as a reason for the return to drug use. Methamphetamine abuse is on the rise yet little in known about the potential role of stress in relapse with this drug of abuse. We are taking a multifaceted approach to examining this issue. Yohimbine is an alpha-2 adrenoreceptor antagonist, and produces anxiogenic, stress-like responses by elevating norepinephrine levels in the brain. We are currently exploring how the relapse provoking effects of yohimbine may interact with neural circuits that may mediate the rewarding aspects of methamphetamine. In our preliminary experiment rats self-administered methamphetamine over the course of two weeks and we collected their brains for analysis following 18 hours or 30 days of withdrawal from drug use. We have found that messenger RNA levels for norepinephrine transporter is reduced in the locus coeruleus at 18 hours of withdrawal and this effect persists for at least 30 days. In addition to norepinephrine transporter, we are examining tyrosine hydroxylase, dopamine transporter and corticotropin releasing factor in neural structures involved in stress and reward. Through these experiments we endeavor to understand how drugs of abuse change the brain and why stress may lead to relapse.